Stephania Libreros, PhD
Anesthesiology, Perioperative and Pain Medicine
Stephania Libreros and Chales N Serhan
Charles N Serhan
Research Category: Allergy, Immunology, Inflammation, and Infectious Diseases
We address the role of physiological hypoxia in the local environment in modulating the resolution of inflammation. Pro-inflammatory lipid mediators including leukotrienes and prostaglandins are produced in pathologic hypoxic tissues, yet the connection between physiologic hypoxic environments and the resolution of inflammation involving lipid mediators remains to be investigated. Here, we present evidence that physiological hypoxic environments, accelerate human M2 macrophage efferocytosis of apoptotic neutrophils and senescent erythrocytes via lipolysis-dependent biosynthesis of Specialized Pro-resolving Mediators (SPMs) (Norris and Libreros et al., PMID: 31681846). SPM biosynthesis was significantly enhanced in human macrophages interacting either neutrophils or erythrocytes and a novel pro-resolving mediator was biosynthesized enabling its structure elucidation. We coined this new molecule, as resolvin E4 (RvE4), since it was derived from the precursor eicosapentaenoic acid (EPA) and contains two separate conjugated diene systems. RvE4 stimulated the efferocytosis of senescent erythrocytes and apoptotic neutrophils. Metabolic targeting enhanced RvE4-SPM biosynthesis. Co-incubations of human macrophages and erythrocytes produced RvE4-SPM from the erythrocyte membrane that served as a novel source for SPMs. RvE4 potently enhanced macrophage efferocytosis and the resolution of hemorrhagic exudates in vivo. Next, we establish the total organic synthesis of RvE4, which confirmed its unique structure and complete stereochemistry, as well as its potent biological functions in human phagocytes (Libreros et al., PMID: 33643307). Together, these results establish a new EPA-derived lipid mediator circuit involved in resolution of inflammation and clearance of senescent cells.
Our research focuses on the discovery of novel immunological signals that occur during inflammation and subsequent resolution. These signals can control local inflammation and stimulate the body’s own endogenous healing mechanisms. The acute inflammatory process is widely accepted to be the body’s first line of defense in response to pathogens or injury and is actively resolved. Emerging evidence indicates that chronic unresolved inflammation is an important underlying cause of numerous complex conditions such as sepsis, arthritis, cardiovascular disease, and cancer, among others. Importantly, it has become evident that pre-existing unresolved inflammatory conditions (i.e., coronary diseases, obesity) are associated with significantly worse outcomes and higher mortality after COVID-19 infections. Here, we discovered a novel molecule called Resolvin E4 that enhances the body’s ability to clear aged cells and to accelerate the resolution of inflammation. We also achieved total organic synthesis of this molecule and demonstrated that its synthetic version has the same potent biological actions as the endogenous molecule made by human cells. The elucidation of novel endogenous resolution mechanisms of inflammation could offer new treatment and prevention strategies to disrupt the damaging cycle of chronic inflammation by facilitating host defense and enhancing tissue repair.